Posts By: Nicola Brunetti-Pierri

Statin treatment for FGFR3 skeletal dysplasia phenotypes.

Posted by & filed under Part 22: CONNECTIVE TISSUE.

A paper published in Nature in September 2014 suggests that statins could represent a medical treatment for infants and children with thanatophoric dysplasia type I (TD1) and achondroplasia (ACH) due to gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3). The authors showed that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) […]

Anti–microRNA-21 oligonucleotides prevent Alport nephropathy

Posted by & filed under Part 24: KIDNEY.

MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys. Highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously have been recently developed. In a murine model of Alport nephropathy, miR-21 silencing resulted in milder kidney disease, with minimal albuminuria and dysfunction. miR-21 silencing dramatically improved […]

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Posted by & filed under Part 18: HORMONES.

A new pediatric disorder (named X-linked acrogigantism [X-LAG]) caused by an Xq26.3 genomic duplication and presenting with early-onset gigantism due to an excess of growth hormone has been described in the Dec 2014 issue of the New England Journal of Medicine. Of the four genes included in the Xq26.3 interval, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients’ […]

Oxytocin restores social behavior in the Cntnap2 mouse model of autism

Posted by & filed under Part 28: NEUROGENETICS.

Mutations in contactin-associated protein-like 2 (CNTNAP2) cause cortical dysplasia and focal epilepsy syndrome. The knockout of the mouse homolog displays many features of the human disorder. The group of Dr. Geschwind performed an in vivo screen for drugs that improve the abnormal social behavior of Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin […]

FGF21 is an endocrine signal of protein restriction

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Several studies have proposed serum fibroblast growth factor 21 (FGF21) levels as a sensitive biomarker of mitochondrial diseases. Serum FGF21 are the best predictor of these disorders when compared to serum levels of classical indicators: creatine kinase, lactate, pyruvate, and the lactate to pyruvate ratio. Enhanced FGF21 production and circulation has been linked to the metabolic adaptation to […]

Deoxypyrimidine monophosphate therapy for thymidine kinase 2 deficiency

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion and/or multiple deletions due to loss of TK2 enzyme activity and unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, Dr. Michio Hirano’s group administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2?/? knock-in mouse model from postnatal day 4, when mutant mice […]

Nuclear Pyruvate Dehydrogenase Complex Generates Acetyl-CoA for Histone Acetylation

Posted by & filed under Part 10: DISORDERS OF MITOCHONDRIAL FUNCTION.

The mitochondrial pyruvate dehydrogenase complex (PDC) is a key enzyme in metabolism but also has a newly recognized functional role in the nucleus of mammalian cells.  Sutendra and colleagues have discovered that PDC translocates from the mitochondria to the nucleus  in a cell-cycle-dependent manner and in response to serum, epidermal growth factor, or mitochondrial stress.  Inhibition of nuclear PDC […]

Recombinant alkaline phosphatase improves bone growth, mineralization and strength in mouse models of neurofibromatosis type-1

Posted by & filed under Part 04: CANCER.

Neurofibromatosis type-1 (NF1) can present with focal skeletal dysplasias that remain extremely difficult to treat. Elefteriou and colleagues report that ablation of Nf1 in bone-forming cells results in accumulation of pyrophosphate (PPi), a strong inhibitor of hydroxyapatite formation, and that a chronic extracellular signal–regulated kinase (ERK)-dependent increase in expression of genes promoting PPi synthesis and extracellular transport, namely Enpp1 […]

Wilson Disease Protein ATP7B Utilizes Lysosomal Exocytosis to Maintain Copper Homeostasis

Posted by & filed under Part 14: METALS.

Copper is an essential metal but its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Polishchuk and colleagues show that, in response to elevated copper, ATP7B moves from the Golgi to […]

MECP2 expression influences aggressive behavior

Posted by & filed under Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

The X-chromosomal MECP2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. MECP2 is mutated in Rett syndrome. This paper found that that mice with ~50% transgenic overexpression of Mecp2 have enhanced aggressive behavior. When the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This […]